ATRA improves endothelial dysfunction in atherosclerotic rabbits by decreasing CAV‑1 expression and enhancing eNOS activity

Wu,Yan; Wang,Xiaobian; Zhou,Qing; Wang,Yi; Zhou,Jiali; Jiang,Qiaoling; Wang,Yuan; Zhu,Huaqing

doi:10.3892/mmr.2018.8647

ATRA improves endothelial dysfunction in atherosclerotic rabbits by decreasing CAV‑1 expression and enhancing eNOS activity

Authors:
- Yan Wu
- Xiaobian Wang
- Qing Zhou
- Yi Wang
- Jiali Zhou
- Qiaoling Jiang
- Yuan Wang
- Huaqing Zhu
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Affiliations: Reproductive Medicine Center, 105 Hospital of People's Liberation Army, Hefei, Anhui 230031, P.R. China, Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China
Published online on: February 27, 2018 https://doi.org/10.3892/mmr.2018.8647
Pages: 6796-6802

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Abstract

The aim of the present study was to explore the protective effects and possible mechanisms of all‑trans‑retinoic acid (ATRA) against atherosclerosis (AS). Rabbits were randomly allocated for standard or high‑fat diet with or without ATRA. After 12 weeks, the aortic rings of the rabbits were removed. Endothelium‑dependent relaxation (EDR) induced by acetylcholine and non‑endothelium‑dependent relaxation induced by sodium nitroprusside in the thoracic aorta were evaluated. NO level and eNOS activity were measured according to the protocol of NO and eNOS ELISA kits. The permeability and morphology of the arterial walls were identified by immunofluorescence and H&E staining respectively. The expression of caveolin‑1 (CAV‑1) and occludin was analyzed using western blotting and immunohistochemistry. The EDR function was significantly reduced in the AS rabbits compared with the normal group, however it was elevated following treatment with ATRA. The eNOS activity and NO level were reduced in the AS group, however were notably increased following oral administration of ATRA. There was an enhancement of endothelial permeability in the AS group compared with the normal group, which decreased following ATRA treatment. Western blot analysis and immunohistochemical analysis identified an increase in occludin expression after treatment with ATRA, in contrast to CAV‑1 expression under the same conditions. ATRA is able to ameliorate high‑fat‑induced AS in rabbits, which is mediated through the activation of eNOS and downregulating CAV‑1 expression.

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1	Fernández-Hernando C, Yu J, Dávalos A, Prendergast J and Sessa WC: Endothelial-specific overexpression of caveolin-1 accelerates atherosclerosis in apolipoprotein E-Deficient mice. Am J Pathol. 177:998–1003. 2010. View Article : Google Scholar : PubMed/NCBI
2	Sima AV, Stancu CS and Simionescu M: Vascular endothelium in atherosclerosis. Cell Tissue Res. 335:191–203. 2009. View Article : Google Scholar : PubMed/NCBI
3	Liu D, He Z, Wu L and Fang Y: Effects of induction/inhibition of endogenous heme oxygenase-1 on lipid metabolism, endothelial function, and atherosclerosis in rabbits on a high fat diet. J Pharmacol Sci. 118:14–24. 2012. View Article : Google Scholar : PubMed/NCBI
4	Zulli A, Buxton BF, Black MJ, Ming Z, Cameron A and Hare DL: The immunoquantification of caveolin-1 and eNOS in human and rabbit diseased blood vessels. J Histochem Cytochem. 54:151–159. 2006. View Article : Google Scholar : PubMed/NCBI
5	Xu Y, Buikema H, van Gilst WH and Henning RH: Caveolae and endothelial dysfunction: Filling the caves in cardiovascular disease. Eur J Pharmacol. 585:256–260. 2008. View Article : Google Scholar : PubMed/NCBI
6	Lee MH, Chen SJ, Tsao CM and Wu CC: Perivascular adipose tissue inhibits endothelial function of rat aortas via caveolin-1. PLoS One. 9:e999472014. View Article : Google Scholar : PubMed/NCBI
7	Luo DX, Cheng J, Xiong Y, Li J, Xia C, Xu C, Wang C, Zhu B, Hu Z and Liao DF: Static pressure drives proliferation of vascular smooth muscle cells via caveolin-1/ERK1/2 pathway. Biochem Biophys Res Commun. 391:1693–1697. 2010. View Article : Google Scholar : PubMed/NCBI
8	Siddikuzzaman, Guruvayoorappan C and Berlin Grace VM: All trans retinoic acid and cancer. Immunopharmacol Immunotoxicol. 33:241–249. 2011. View Article : Google Scholar : PubMed/NCBI
9	Axel DI, Frigge A, Dittmann J, Runge H, Spyridopoulos I, Riessen R, Viebahn R and Karsch KR: All-trans retinoic acid regulates proliferation, migration, differentiation, and extracellular matrix turnover of human arterial smooth muscle cells. Cardiovasc Res. 49:851–862. 2001. View Article : Google Scholar : PubMed/NCBI
10	Herdeg C, Oberhoff M, Baumbach A, Schroeder S, Leitritz M, Blattner A, Siegel-Axel DI, Meisner C and Karsch KR: effects of local all-trans-retinoic acid delivery on experimental atherosclerosis in the rabbit carotid artery. Cardiovasc Res. 57:544–553. 2003. View Article : Google Scholar : PubMed/NCBI
11	Uruno A, Sugawara A, Kanatsuka H, Kagechika H, Saito A, Sato K, Kudo M, Takeuchi K and Ito S: Upregulation of nitric oxide production in vascular endothelial cells by all-trans retinoic acid through the phosphoinositide 3-kinase/Akt pathway. Circulation. 112:727–736. 2005. View Article : Google Scholar : PubMed/NCBI
12	Cho DH, Choi YJ, Jo SA, Nam JH, Jung SC and Jo I: Retinoic acid decreases nitric oxide production in endothelial cells: A role of phosphorylation of endothelial nitric oxide synthase at Ser(1179). Biochem Biophys Res Commu. 326:703–710. 2005. View Article : Google Scholar
13	Drolet MC, Plante E, Battistini B, Couet J and Arsenault M: Early endothelial dysfunction in cholesterol-fed rabbits: A non-invasive in vivo ultrasound study. Cardiovasc Ultrasound. 2:102004. View Article : Google Scholar : PubMed/NCBI
14	Yang AL, Yeh CK, Su CT, Lo CW, Lin KL and Lee SD: Aerobic exercise acutely improves insulin and insulin-like growth factor-1-mediated vasorelaxation in hypertensive rats. Exp Physiol. 95:622–629. 2010. View Article : Google Scholar : PubMed/NCBI
15	Bushue N and Wan YJ: Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev. 62:1285–1298. 2010. View Article : Google Scholar : PubMed/NCBI
16	Ye Xf, Wu Q, Liu S, Lin Xf, Zhang B, Wu Jf, Cai Jh, Zhang Mq and Su Wj: Distinct role and functional mode of TR3 and RARalpha in mediating ATRA-induced signalling pathway in breast and gastric cancer cells. Int J Biochem Cell Biol. 36:98–113. 2004. View Article : Google Scholar : PubMed/NCBI
17	Zhou B, Pan Y, Hu Z, Wang X, Han J, Zhou Q, Zhai Z and Wang Y: All-trans-retinoic acid ameliorated high fat diet-induced atherosclerosis in rabbits by inhibiting platelet activation and inflammation. J Biomed Biotechnol. 2012:2596932012. View Article : Google Scholar : PubMed/NCBI
18	Hansson GK, Robertson AK and Söderberg-Nauclér C: Inflammation and atherosclerosis. Annu Rev Pathol. 1:297–329. 2006. View Article : Google Scholar : PubMed/NCBI
19	Sitia S, Tomasoni L, Atzeni F, Ambrosio G, Cordiano C, Catapano A, Tramontana S, Perticone F, Naccarato P, Camici P, et al: From endothelial dysfunction to atherosclerosis. Autoimmun Rev. 9:830–834. 2010. View Article : Google Scholar : PubMed/NCBI
20	Simionescu M and Antohe F: Functional ultrastructure of the vascular endothelium: Changes in various pathologies. Handb Exp Pharmacol. 41–69. 2006. View Article : Google Scholar : PubMed/NCBI
21	Mehta D and Malik AB: Signaling mechanisms regulating endothelial permeability. Physiol Rev. 86:279–367. 2006. View Article : Google Scholar : PubMed/NCBI
22	Yuan SY: Protein kinase signaling in the modulation of microvascular permeability. Vascul Pharmacol. 39:213–223. 2002. View Article : Google Scholar : PubMed/NCBI
23	Shepro D: The american microcirculatory society landis award lecture: Endothelial cells, inflammatory edema, and the microvascular barrier: Comments by a ‘free radical’. Microvasc Res. 35:246–264. 1988. View Article : Google Scholar : PubMed/NCBI
24	Suzuki H, Nishizawa T, Tani K, Yamazaki Y, Tamura A, Ishitani R, Dohmae N, Tsukita S, Nureki O and Fujiyoshi Y: Crystal structure of a claudin provides insight into the architecture of tight junctions. Science. 344:304–307. 2014. View Article : Google Scholar : PubMed/NCBI
25	McKenzie JA and Ridley AJ: Roles of Rho/ROCK and MLCK in TNF-alpha-induced changes in endothelial morphology and permeability. J Cell Physiol. 213:221–228. 2007. View Article : Google Scholar : PubMed/NCBI
26	Zhao J, Hao J, Fei X, Wang X, Hou Y and Deng C: Isoflurane inhibits occludin expression via up-regulation of hypoxia-inducible factor 1α. Brain Res. 1562:1–10. 2014. View Article : Google Scholar : PubMed/NCBI
27	Dias RG, Negrão CE and Krieger MH: Nitric oxide and the cardiovascular system: Cell activation, vascular reactivity and genetic variant. Arq Bras Cardiol. 96:68–75. 2011.PubMed/NCBI
28	Verma S, Buchanan MR and Anderson TJ: Endothelial function testing as a biomarker of vascular disease. Circulation. 108:2054–2059. 2003. View Article : Google Scholar : PubMed/NCBI
29	Achan V, Tran CT, Arrigoni F, Whitley GS, Leiper JM and Vallance P: All-trans-retinoic acid increases nitric oxide synthesis by endothelial cells: A role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res. 90:764–769. 2002. View Article : Google Scholar : PubMed/NCBI
30	Figueroa XF, González DR, Puebla M, Acevedo JP, Rojas-Libano D, Durán WN and Boric MP: Coordinated endothelial nitric oxide synthase activation by translocation and phosphorylation determines flow-induced nitric oxide production in resistance vessels. J Vasc Res. 50:498–511. 2013. View Article : Google Scholar : PubMed/NCBI
31	Trane AE, Pavlov D, Sharma A, Saqib U, Lau K, van Petegem F, Minshall RD, Roman LJ and Bernatchez PN: Deciphering the binding of caveolin-1 to client protein endothelial nitric-oxide synthase (eNOS): Scaffolding subdomain identification, interaction modeling, and biological significance. J Biol Chem. 289:13273–13283. 2014. View Article : Google Scholar : PubMed/NCBI
32	Du YH and Chen AF: A new role for caveolin-1: Regulation of guanosine triphosphate cyclohydrolase I and tetrahydrobiopterin in endothelial cells. Hypertension. 53:115–117. 2009. View Article : Google Scholar : PubMed/NCBI